Metoprolol is a beta1-selective (cardioselective) adrenoceptor blocking agent, available as immediate and extended-release tablets as well as for injection. Examples of beta-adrenergic blockers include propanolol (Inderal, Inderal LA, Innopran XL), atenolol (Tenormin), and timolol (Blocadren). Metoprolol blocks the action of the sympathetic (involuntary) nervous system by blocking beta receptors on sympathetic nerves. Since the sympathetic nervous system is responsible for increasing the rate with which the heart beats, by blocking the action of these nerves metoprolol reduces the heart rate and is useful in treating abnormally rapid heart rhythms.
Metoprolol is selective, moderately lipophilic, without intrinsic sympathomimetic activity, has weak membrane stabilizing activity, and has a short half-life, and therefore must be taken at least twice daily or as a slow-release preparation.
TOPROL-XL® is an extended-release tablet of metoprolol succinate sold by Astra Zeneca and intended for once daily administration. TOPROL-XL® has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. Its chemical name is (±)1(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Inactive Ingredients in Toprol XL® include silicon dioxide, sodium stearyl fumarate, polyethylene glycols, titanium dioxide, paraffin, and hypromethylcellulloses. (Toprol XL® label).
Metoprolol tartrate is available in the USA as immediate release tablets for oral administration and in ampuls for intravenous administration. Each ampul contains a sterile solution of metoprolol tartrate, sodium chloride, and water for injection. Metoprolol tartrate is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt.
Metoprolol has a very low melting point, tartrate around 120° C., succinate around 136° C. Because of this, metoprolol is always manufactured in a salt-based solution, as drugs with low melting points are difficult to work with in a manufacturing environment. The free base exists as a waxy white solid, and the tartrate salt is finer crystalline material. Metoprolol is metabolized in the liver to inactive metabolite and undergoes a-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6 and a small percentage by CYP3A4.
Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. Metoprolol succinate is a classic example of a BCS (Biopharmaceutics Classification System) class 1 drug which is highly soluble and has high permeability and is well absorbed and its absorption rate is higher than excretion. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether and heptane.
Metoprolol tartrate is a white, practically odorless, crystalline powder with a molecular weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether.
Metoprolol reduces the force of contraction of heart muscle and thereby lowers blood pressure. By reducing the heart rate and the force of muscle contraction, metoprolol reduces the need for oxygen by heart muscle. Since heart pain (angina pectoris) occurs when oxygen demand of the heart muscle exceeds the supply of oxygen, metoprolol, by reducing the demand for oxygen, is helpful in treating heart pain
Metoprolol succinate is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol.
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Metoprolol succinate may be administered with other antihypertensive agents.
Metoprolol succinate is also indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. Metoprolol succinate is also indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, Metoprolol succinate decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.
Metoprolol is marketed under the brand name Lopressor® by Novartis, and Toprol-XL® by AstraZeneca (in the USA); Selokeen® (in the Netherlands); as Minax® by Alphapharm (in Australia), Metrol® by Arrow Pharmaceuticals (in Australia), as Betaloc® byAstraZeneca, as Bloxan® by Krka (company) (in Slovenia), as Neobloc® by Unipharm (in Israel), Presolol® by Hemofarm (in Serbia) and as Corvitol® by Berlin-Chemie AG (in Germany). In India, this drug is available under the brand names of Met-XL®, Metolar® and Starpress, Restopress®.
Controlled-release formulations have been one of the major focuses in pharmaceutical research and development. Matrix systems are a very attractive approach in controlled-release systems.
The advantages of controlled release products are well known in the pharmaceutical field. Sustained release drug formulations may be useful to reduce the frequency of drug administration (especially in the case of drugs with short compound half lives such as metoprolol), improve patient compliance, reduce drug toxicity (local or systemic associated with high peak exposure), reduce drug level fluctuation in blood, stabilize medical condition with more uniform drug levels, reduce drug accumulation with chronic therapy, improve bioavailability of some drugs because of spatial control, and reduce total drug usage when compared with immediate release drugs.
Mechanical devices aside, interaction between a drug and a polymeric material usually forms the basis of controlled oral drug delivery. A polymer at certain concentrations in a solution imposes pathways for drug diffusion. Polymers that dissolve in or otherwise hydrate in aqueous media can alter the drug diffusion process in a time-dependent manner. For example, a commonly used material, hydroxypropyl methylcellulose (HPMC), which is water soluble, behaves as a swellable absorptive polymer in the limited volumes of aqueous media in the gastrointestinal tract. Drug dispersed in this polymer, as in monolithic tablets, diffuses through the viscous hydrated polymer at a rate dependent on the movement kinetics of the polymer chains. The faster these relax, the faster the diffusion rate.
Development of dosage form depends on chemical nature of the drug and polymers, the matrix structure, swelling, diffusion, erosion, the release mechanism and the in vivo environment.
Hydrophilic polymers like HPMC may also control drug release by erosion mechanisms. After consumption of the dosage form, the GI tract fluid encounters the dosage unit, causing the polymer to hydrate and swell. Weakened mechanical properties in the swollen state may cause the hydrated polymer to break away from the prime particle (compact or pellet). Drug release may therefore be controlled by a combination of diffusion and erosion. Such release mechanisms can apply to systems where drug is dispersed in or coated with polymer.
Delivery to specific regions of the GI tract may be achieved using polymers with pH-dependent solubilities. These include enteric polymers with carboxylic acid functional groups; their pH-dependent solubility determines location for release.
Water insoluble polymers can extend drug release. These include methacrylate- or acrylate-based polymers with low permeability.
Hydrophilic functional groups such as trimethylaminoethyl methacrylate can improve permeability and swellability in water thus altering release behaviors. Technologies have been developed to exploit diffusion, erosion, and other physicochemical mechanisms and provide drug and disease-specific release profiles. Examples include the release from a Contramid™ tablet controlled by the degree of crosslinking of high amylase starch and Alza's Oros™ and Duros™ technologies are based on osmosis-driven release.
Different hydrogels have been described for use in controlled release medicines, most of which are semi-synthetic or of natural origin. A few contain both synthetic and non-synthetic material. However, many of the systems require special process and production equipment, and in addition some of these systems are susceptible to variable drug release.
Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and temporal requirements. While many controlled and sustained-release formulations are already known, certain soluble to highly soluble drugs present formulation difficulties when included in such formulation. An example of such a highly soluble drug is metoprolol. There have been a number of patents in the prior art which relate to controlled release metoprolol formulations and yet the successful extended release versions of metoprolol succinate currently consist of complex, expensive multiparticulate formulations such as that of Toprol XL®.
U.S. Pat. No. 5,169,638 describes a buoyant controlled release pharmaceutical formulation in the form of a powder filled capsule in which an active ingredient of a basic character exhibits a pH-independent controlled release. The powder comprises the active agent, which may be metoprolol, a water-soluble salt of polyuronic acid, a pH-independent hydrocolloid gelling agent (e.g., hydroxypropylmethylcellulose, methylcellulose or hydroxypropylcellulose), and a binder (HPMC). The formulation is free of calcium ion and carbon dioxide producing material and is said to float gastric juices so that it will have extended residence time in the stomach in contrast to the instant invention which preferably provides colonic release.
U.S. Pat. No. 5,399,362 describes a sustained release oral solid dosage form of metoprolol including a gelling agent, an inert pharmaceutical diluent, a cationic cross-linking agent. The formulation provides release of metoprolol for at least about 24 hours.
U.S. Pat. No. 4,957,745 also describes a controlled release metoprolol. The preparation includes a plurality of beads comprising metoprolol coated with a polymeric membrane comprising ethylcellulose with or without hydroxypropylmethylcellulose.
U.S. Pat. No. 4,871,549 describes a time controlled explosion system comprising metoprolol, a swelling agent such as a low substituted hydroxypropylcellulose, sodium starch glycolate or carboxymethylcellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period.
U.S. Pat. No. 5,081,154 is directed to metoprolol succinate in an oral composition coated with an anionic polymer soluble at pH over 5.5 and a water insoluble quaternary ammonium substituted acrylic polymer.
U.S. Pat. No. 4,792,452 describes controlled release pharmaceutical compositions which are said to provide pH-independent release for a basic drug such as metoprolol. The formulations include a pH-dependent polymer which is a salt of alginic acid, a pH-independent hydrocolloid gelling agent and a binder. The salt of the alginic acid is preferably sodium alginate or potassium alginate. The weight ratio of the alginic acid salt to the hydrocolloid gelling agent is all within the range 0.1:1 to 10:1, and the formulation is free of calcium ion and carbon dioxide-producing material.
There is a metoprolol formulation marketed in the United Kingdom called Betaloc®S.A., which contains 200 mg of metoprolol tartrate in a controlled release matrix. Metoprolol is available as 50 mg, 100 mg and 200 mg extended release tablets in the United States and is marketed under the name Toprol XL® from AstraZeneca. Toprol XL® tablets contain the succinate salt of metoprolol (equivalent to 50 mg, 100 mg and tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. These tablets may be dosed once daily. Studies have shown that formulations similar to those of Toprol XL®, containing metoprolol succinate in a multitude of controlled release pellets, has a more sustained time profile of beta-blockade at steady-state than formulations similar to those of Betaloc® S.A., containing metoprolol tartrate in a controlled release matrix. See, e.g., Berend Oosterhuis, PhD, et al., “A Pharmacokinetic and Pharmacodynamic Comparision of Metoprolol CR ZOK with a Conventional Slow Release Preparation,” J Clin. Pharmacol., 1990:30:533-538. Additionally, these studies have shown that metoprolol succinate in an extended release form similar to Toprol XL® had mean and individual plasma concentration-time profiles that were said to be smoother than the profiles of formulations such as those of Betaloc® S.A. Further, for formulations containing metoprolol succinate in a controlled release form similar to Toprol XL®, the value of Cmax was significantly lower, the Cmm was higher, the Tmax value tended to be longer, and the time during which the metoprolol plasma concentration exceeded 75% of Cmax was significantly longer versus formulations, similar to those of Betaloc®S.A. containing metoprolol tartrate in a controlled release matrix.
Furthermore, the process employed to create the multitude of controlled-release pellets of Toprol XL® is more complex and time consuming than a monolithic matrix formulation.
In the USA, Metoprolol tartrate (Lopressor) is a regular, immediate-release tablet, while metoprolol succinate (Toprol XL®) is an extended-release tablet. A shortage of generic metoprolol succinate has necessitated switching some patients to alternative therapy. An option for some patients is metoprolol tartrate (Lopressor and its generics) but there are differences between metoprolol tartrate and metoprolol succinate. Metoprolol tartrate is usually dosed twice daily. It can be effective for hypertension when dosed once daily, but low doses (e.g., 100 mg) given once daily may not control blood pressure for a full 24 hours. Metoprolol succinate is dosed once daily. Metoprolol succinate produces more level metoprolol concentrations than the immediate-release tablets (i.e., lower peaks and less peak-to-trough variation). Metoprolol tartrate is at least 30% more bioavailable than metoprolol succinate (i.e., more drug is absorbed). However, overall 24 hour betablockade is comparable at the same dose. PHARMACIST'S LETTER/PRESCRIBER'S LETTER March 2009˜Volume 25˜Number 250302
Accordingly, there exists a need in the art to provide a monolithic, matrix-based sustained release oral dosage form that provides for the sustained release of metoprolol succinate suitable for once-a-day administration.